Transient receptor potential cation channel subfamily M member 4 (TRPM4), also known as melastatin-4, PFHB1B, TRPM4B or LTrpC4, is a protein that in humans is encoded by the TRPM4 gene, which is located at the chromosome 19q13.33. TRPM4 shows a three-tiered architecture because of multiple transmembrane and cytosolic domains. It contains an N-terminal nucleotide-binding domain, which can bind ATP to inhibit channel activity; a C-terminal coiled-coil participating in the tetrameric assembly of the channel. TRPM4 has a wide expression in colon, prostate, small intestine, stomach, duodenum, skin, and multiple other tissues.
|Basic Information of TRPM4|
|Protein Name||Transient receptor potential cation channel subfamily M member 4|
|Aliases||PFHB1B, TRPM4B, LTrpC4|
|Organism||Homo sapiens (Human)|
TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-modulated, non-selective cation channel
. Activation of TRPM4 can depolarize the plasma membrane through Na⁺ entry, which in turn enhances Ca²⁺ influx through Ca²⁺-permeable channels or otherwise modulates Ca²⁺ oscillations. It plays a role in myogenic constriction of cerebral arteries. Unlike many other TRP channels, TRPM4 is permeable to monovalent cations only. In pancreatic β-cells, it directly controls the secretion of insulin. TRPM4 can also affect cell motility of T-helper 1 (Th1) and T-helper 2 (Th2) and intervene in its cytokine production through the differential mediation of NFATC1 localization and calcium signaling. The expression of beta-catenin can be upregulated by TRPM4 and consequently lead to the enhancement of cell proliferation. In addition, TRPM4 is associated with cardiovascular disorders.
Fig.1 Cryo-EM structure of a human TRPM4 channel in complex with calcium and decavanadate. (Winkler, 2017)
This article demonstrates that TRPM4 channels are associated with overactivity of detrusor smooth muscle following spinal cord transection in mice, suggesting that repression of TRPM4 may be of benefit for improving it.
This article confirms that TRPM4 is important from early stages of murine experimental autoimmune encephalomyelitis, and suggests that use of these more efficient TRPM4 inhibitors could be novel protective therapeutic methods to treat glutamate-induced neurodegeneration.
This article indicates that protein tyrosine phosphatase non-receptor type 6 (PTPN6)-dependent TRPM4 expression and its trafficking to the plasma membrane are crucial for cell proliferation in both HeLa cells and HEK293, suggesting that PTPN6 may be a novel therapeutic target for the treatment of pathologic diseases involving TRPM4.
This report suggests that increased or decreased expression of several TRPM4 variants linked to ventricular arrhythmias or cardiac conduction disorders is found to be caused by the changed half-life of TRPM4 in contrast with the wild-type form.
This article determines human full-length TRPM4’s apo structure by cryo-EM with densities in its conduction pathway that is very likely to be Na⁺ ions.
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